Diaminopyrimidines as P2X3 and P2X2/3 modulators

Abstract

Compounds and methods for treating diseases mediated by a P2X 3 and/or a P2X 2/3 receptor antagonist, the compounds being of formula (I): wherein D, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.

1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         X is:
 —O—; 
 
         R 1  is: isopropyl; 
         R 2 , R 5  and R 6  are hydrogen; 
         R 3  is alkoxy; 
         R 4  is halo or —C═C—R a — wherein R a  is hydrogen; 
         one of R 7  and R 8  is hydrogen and the other is R 9 , or both R 7  and R 8  are R 9 : and 
         each R 9  is independently:
 —(C═O)—R d ; 
 —(O═)P(OR g ) 2 ; 
 —S(═O) 2 OR g ; or 
 a mono-, di- or tri-peptide, 
 wherein
 R d  is alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, heterocyclyloxy, —(CH 2 ) p —C(═O)—R e , —(CH═CH)—C(═O)—R e , or —CH(NH 2 )—R f ; 
 wherein
 R e  is hydrogen, hydroxy, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, cycloalkyloxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy or heterocyclyloxy; 
 p is 2 or 3; 
 R f  is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, optionally substituted phenyl, benzyl, guanidinylalkyl, carboxyalkyl, amidoalkyl, thioalkyl or imidazolalkyl; and 
 R g  is hydrogen, alkyl, an alkali metal ion or an alkaline earth metal ion. 
 
 
 
       
     
     
       2. The compound of  claim 1 , wherein R 4  is iodo. 
     
     
       3. The compound of  claim 1 , wherein one of R 7  and R 8  is hydrogen and the other is R 9 , R 9  is —(C═O)—R d , and R d  is alkyl, alkoxy, heteroaryl or heterocyclyl. 
     
     
       4. The compound of  claim 1  wherein said compound is of the formula (II): 
       
         
           
           
               
               
           
         
       
       wherein X, R 1 , R 3 , R 4 , R 7  and R 8  are as recited in  claim 1 . 
     
     
       5. The compound of  claim 4 , wherein R 4  is iodo. 
     
     
       6. The compound of  claim 5  wherein one of R 7  and R 8  is hydrogen and the other is R 9 , R 9  is —(C═O)—R d , and R d  is alkyl, alkoxy, heteroaryl or heterocyclyl. 
     
     
       7. A pharmaceutical composition comprising:
 (a) a pharmaceutically acceptable carrier; and 
 (b) a compound of  claim 1 .